Fluorinated tricyclic neuroleptics with prolonged effects: Some new 8-chloro-3-fluoro-10-piperazino-10,11-dihydrodibenzo[b,f]thiepins

Abstract

Six new 8-chloro-3-fluoro-10-piperazino-lO,1l-dihydrodibenzo[b,f]thiepins II-VII were synthesized, amino alcohol II being a highly effective neuroleptic and tranquilizer in acute tests, dioxolane IV prolonging these effects upon oral administration. A new synthesis of acid VIII was developed, proceeding via (2-bromo-4-fluorophenyl)acetic acid (XI). A second geometric isomer of the 3--fluoro derivative of chloroprothixene (XIII) was prepared which, according to the IR spectrum, is of cis-configuration; it is inactive cataleptically and only a weak depressant. Acids XIVab were synthesized using selective bromination of phenylacetamide in the ortho-position. Starting from acid XIVa and via the intermediate XVIIa, 1-[2-(2-p-chlorophenylthiophenyl)-ethyl]-4-methylpiperazine (XIXa) was prepared, a new open model of octoclothepin which acted as an anticonvulsant and showed signs of antihistamine effects.In a previous communication! we described the synthesis of the 3-fluoro derivative of octoclothepin (I) which displayed a high degree of neuroleptic and depressant activity on oral application in acute tests and clear signs of prolongation of these effects. This was explained by a block of metabolic hydroxylation of the octoclothepin molecule by fluorination 1 ,2. The work has now been extended to include several analogues of I with modified N-substituents. Firstly, amino alcohol II was synthesized, this being a 3-fluoro derivative of the highly active noroxyclothepin 3 -5. It was prepared by a substitution reaction of 8, 1O-dichloro-3-fluoro-l 0, l1-dihydrodibenzo[b,f]-thiepinl with 1-(2-hydroxyethyl)piperazine. Its esterification with decanoyl chloride 6 (for method see 4 ) yielded the ester III which is a 3-fluoro derivative of the depot neuroleptic noroxyclothepin decanoate 4 ,7 ,8. Further prepared were IV and V with a 1,3-dioxolane or 4-methyl-l,3-dioxolane residue in the side chain; these are 3-fluoro derivatives of previously prepared octoclothepin analogues 9 which displayed, in comparison with octoclothepin, a much lower toxicity on oral administration. The purpose of synthesis of IV and V was to prepare oral neuroleptics with prolonged effect that would be less toxic than the 3-fluoro derivative of octoclothepin (I). ForPart CXIII in the series Neurotropic and Psychotropic Agents; Part CXI1: This Journal 42,2240 (1977).

Butaclamol-like neuroleptic agents: Synthesis of 1-(11H-dibenz[b,f]-1,4-oxathiepin-11-yl)methyl-4-isobutylpiperidin-4-ol and of some related compounds

“…Similar reactions were described in our previous communications 9 -12 • 4-Hydroxypiperidine 13 -17 , which should react in the mentioned attempt, I III, X= CHI IV, X= S was ohtained insttad of the wanted 4-isobutylpipcridin-4-ol by reaction of l-ethoxycarbonyl-4-piperidone 18 with isobutylmagncsium bromide in ether and by the following hydrolysis of the crude product with potassium hydroxide in boiling ethanol; the Grignard reagent only reduced the ketone. Similar r(suIts gave reactions of I-el hoxycarbonyl-4-piperidone 18 with isopropylmagnesium chloride or with tcrt--butyl magnesium chloride and the following alkaline hydrolyses: only mixtures of the desired tertiary alcohols with prevailing 4-hydroxypipcridine we re obtained.…”

Regioisomerism in the Synthesis of a Chiral Aminotetralin Drug Compound: Unraveling Mechanistic Details and Diastereomer-Specific In-Depth NMR Investigations

“…Homing in on the underlying cause for the impurity profile thus observed, our attention was devoted to the very first step in the sequence, which is common to both second- and third-generation routes. In this literature-based method, the aromatic carboxylic acid starting material 2a was treated with elemental Br 2 (slight excess of 2.5 mol %) in the presence of K 2 CO 3 as base under aqueous conditions . After an extractive workup was conducted, the crude product was isolated and the analysis revealed a relative composition (HPLC) of monobromo isomers 4a – c of 55/34/8 (total yield 30–35%), respectively, besides a minor amount (1%) of the dibrominated species 4d .…”

Construction of a Chiral Central Nervous System (CNS)-Active Aminotetralin Drug Compound Based on a Synthesis Strategy Using Multitasking Properties of ( S)-1-Phenylethylamine

“…Some important features observed when developing this route warrant further discussion. In the first stage, acid 4 , commercially available in bulk amounts, is brominated using Br 2 in an aqueous system under basic conditions (K 2 CO 3 ) . This procedure produces a mixture of mono-bromo regioisomers in a typical ratio between the 2-bromo-5-methyl (desired isomer, 5 )/4-bromo-3-methyl/2-bromo-3-methyl derivatives, respectively, of 4:2:1.…”

“…In the first stage, acid 4, commercially available in bulk amounts, is brominated using Br 2 in an aqueous system under basic conditions (K 2 CO 3 ). 9 This procedure produces a mixture of mono-bromo regioisomers in a typical ratio between the 2-bromo-5-methyl (desired isomer, 5)/4-bromo-3methyl/2-bromo-3-methyl derivatives, respectively, of 4:2: 1. Fortunately, the structural similarity of these components did not prevent an effective purification method to be developed, and therefore, two consecutive recrystallizations from water-based systems containing i-PrOH and HOAc managed to generate material (5) 10 in high purity (98%) at yields in the range of 30-35%.…”